Dangers Of Isoflavones In
Soy And Soy-Based Foods
From Jane Jones
jane@npwa.freeserve.co.uk
10-6-2

Who knew what - and when?

The studies are easily found by doing a Pubmed search.

DANGERS OF DIETARY ISOFLAVONES AT LEVELS ABOVE THOSE
FOUND IN TRADITIONAL DIETS

Cargill has received "self-determined" GRAS
status for its AdvantaSoyTMClearTM isoflavone supplement to be used as
an additive for beverages, nutrition bars, yoghurt, meal replacements and
confections. The summaries of studies attached give ample demonstration
of the dangers of adding phytoestrogens (isoflavones) to common foods.
Deleterious effects include endocrine disruption, thyroid suppression,
immune system suppresion and increased incidence of leukemia, breast cancer,
colon cancer, infertility, growth problems and subtle changes in sexually
dimorphic behaviors.

It has been argued that high levels of soy isoflavones
such as genistein, daidzein and genistin in Asian diets protect the inhabitants
of Japan and China from certain degenerative diseases, especially breast
and prostate cancer. Actually, consumption of soy in traditional Asian
diets is low. A 1975 report lists soyfoods as minor sources of protein
in Japan and China.(1) Major sources of protein listed were meat including
organ meats, poultry, fish and eggs. Average isoflavone consumption in
Asian diets ranges from 10-28 mg/day, as shown in the table below. Studies
indicate that isoflavone consumption at levels slightly exceeding those
found in traditional diets results in thyroid suppression and endocrine
disruption.

The AdvantaSoyTMClearTM supplement would add 30-50 mg
of isoflavones to a 100-gram serving of various common foods, levels that
exceed the amounts found in traditional diets and that are in the range
of levels shown to cause problems, especially for sensitive individuals.
It is not only possible but likely that many individuals will consume
two or more servings of foods to which the Cargill isoflavones have been
added, especially as these foods will be promoted with much advertising
touting their health benefits. Two or more servings of such foods would
provide 60-100 mg isoflavones per day, an amount that clearly poses dangers
after only a brief period of daily intake.

As evidence on the toxicity of soy isoflavones accumulates,
warnings have begun to appear in the popular press. An article appearing
in the Washington Post Health Section was titled: "You have to be
soy careful: tofu and similar foods may be beneficial, but some experts
fear that too much could be unsafe."8 Writing for the New York Times,
health columnist Marian Burros published the following: "Against the
backdrop of widespread praise. . . there is growing suspicion that soy-despite
its undisputed benefits-may pose some health hazards. . . . Not one of
the 18 scientists interviewed for this column was willing to say that taking
isoflavones was risk free."9

The addition of isoflavones to common foods poses a clear
danger to the public and should not be allowed.

4. Nakamura Y, Tsuji S, Tonogai Y. Determination of
the levels of isoflavonoids in soybeans and soy-derived foods and estimation
of isoflavonoids in the Japanese daily intake. J AOAC Int 2000;83:635-650.

5. This exhaustive study of Chinese diets found that
legume consumption ranged from 0 to 58 grams per day, with an average of
13 gams. Assuming that two-thirds of this is from soy beans, then consumption
averages about 9 grams of soy products per day. Isoflavone content would
be about 10 mg/day. Chen J, Campbell TC, Li J, Peto R. Diet, Lifestyle
and Mortality in China. A study of the characteristics of 65 counties.
Monograph, joint publication of Oxford University Press, Cornell University
Press, China People's Medical Publishing House. 1990.

1953 Cheng C and others. Estrogenic Activity of Isoflavone
Derivatives Extracted and Prepared from Soybean Meal. Science 1953;118:164-5.
Feeding 2.5 or 5.0 mg of either genistein or genistin per day to the mouse
resulted in increased uterine weights.

1954 Carter and others. Effect of Genistin on Reproduction
of the Mouse. J Nutr 1954;55:639. Exposure to the phytoestrogen genistin
caused significant advancement of the vaginal opening and a decrease in
the number of litters born.

1956 Matrone G and others. Effect of Genistin on Growth
and Development of the Male Mouse. J Nutr, 1956, 235-240. "The evidence
presented indicates that genistin at certain dose levels has a detrimental
effect on survival, growth rates and spermatogenesis in mice. . . the higher
dose appeared to be lethal. It appears that genistin in relation to its
estrogenic activity has a greater depressing effect on growth than does
stilbestrol."

1962 Wong E in "Jour of Endocrinology" "Estrogenic
Activity of Red Clover Isoflavones and Some of Their Degradation Products"
This was a comparative in vivo (mice on uterine effects) study of the estrogenic
effects of several red clover isoflavones "The bioassays showed that
genistein was the most potent of the isoflavones".

1963 Magee AC. Biological Responses of Young Rats Fed
Diets Contain Genistin or Genistein. J Nutr 1963;80:151. A dietary level
of 0.5% genistin or genistein resulted in significant decreases in weight
gain and in the weights of kidneys and spleen.

1963 Noteboom and Gorski. Estrogenic Effects of Genistein
and Coumestrol Diacetate. "It is quite likely that plant estrogens
perform the same function as estradiol in triggering anabolic responses.
The results of these experiments indicate that certain of the nonsteroidal
estrogenic compounds are capable of stimulation of labelled precursors
into protein, lipid and ribonucleic acid in the cells of the rat uterus."

1966 Folmon Y and others. The interaction in the Immature
Mouse of Potent Estrogens with Coumestrol, Genistein and other Utero-Vaginotropic
Compounds of Low Potency. J Endrocrin 1966;34:215-225. Phytoestrogens such
as genistein are said to be of "weak" potency. This study found
that sometimes these estrogens were additive at very small doses and appeared
to be antagonistic at higher doses. "Genistein gave a steep dose-response
curve with high responses (uterus weight near 45 grams) typical of the
most potent estrogens."

1967 Braden and others. The oestrogenic activity and
metabolism of certain isoflavones in sheep. Australian Journal of Agricultural
Research 1967, 18:335-348. "Some plants that are commonly grazed nevertheless
contain substances that are harmful to the animals ingesting them and one
group of such compounds (phyto-estrogens) can cause reproductive disorders
in females."

1972 Shutt DR. Steroid and Phytoestrogen Binding to Sheep
Uterine Receptors in Vitro. J Endocrin 1972;52:299-305. Phytoestrogens
were found to compete with estradiol for binding sites. "A full estrogenic
response is elicited only when they are given in repeated frequent doses,
which may be necessary to maintain a high blood concentration."

1975 Farnsworth NR and others in Jour of Pharmaceutical
Sciences "Potential Value of Plants as Anti-fertility Agents".
"Phytochemical interest in plant estrogensincreased in the 1950s
due to the recognition that infertility in animals and humans could follow
excessive ingestion of plants rich in estogenic activity" Genistein
and Daidzein were identified in soybeans ' A large reduction in sperm numbers
was observed in prolonged grazing of sheep in clover pasture'." Genistein
has a remarkable structural similarity to DES"

1976 "Chemical Carcinogens"a text book published
by the American Chemical Society at pages 658 - 664 " The younger
the animal the more susceptible it is to the action of estrogens., as it
frequently is to other carcinogens" 1977 Leopold AS and others. Phytoestrogens:
Adverse effects on reproduction in California Quail. Science, 1976 Jan
9;191(4222): 98-100. During dry years, phytoestrogens, including genistein,
are produced in the leaves of stunted desert annuals. When ingested by
California quail, these compounds apparently inhibit reproduction and prevent
the production of young that will not have adequate food. In a wet year,
forage grows vigorously and phytoestrogenic substances are largely absent.
Quail then breed prolifically and the abundant seed crop carries the enlarged
population through the winter.

1976 Kimura S and others. Development of malignant
goiter by defatted soybean with iodine-free diet in rats. Gann 1976, 67:763-765.
Iodine-deficient rats fed defatted soybean for 6 to 12 months developed
enlarged goiters and malignant thyroid tumors. Thyroid enlargement was
inhibited with the addition of small amounts of iodine to the diet.

1976 Shutt DR. The Effects of Plant Estrogens in Animal
Reproduction. Endeavour 1976:110-113. "In high concentrations, a weak
plant estrogen can exert a significant estrogenic effect in the animal
and can product hormonal imbalance. . . when high blood concentrations
are maintained, they can exert a maximal estrogenic effect. . . From the
wider viewpoint of evolution, it is interesting that compounds have evolved
in plants that not only give the plant some protection from pathogens,
but also reduce fertility of animals ingesting the plant."

1976 Lindner HR. Occurrence of Anabolic Agents in Plants
and their Importance. Environment Quality Supplement 1976;5:151-158. "Coumestrol
and genistein stimulate estradiol in stimulating macromolecular changes
in the uterus. The biological effects of clover estrogens responsible for
fertility impairment appear to be multiple."

1978 Martin PM and others. Phytoestrogen interaction
with estrogen receptors in human breast cancer cells. Endocrinology 1978
Nov;103(5):1860-7. Phytoestrogens "translocate the cytoplasmic estrogen
receptor and bind to unfilled nuclear estrogen receptors in whole cells.
Bound nuclear receptors are then processed in a manner similar to estradiol
in a step which rabidly decreases total cellular estrogen receptors. The
phytoestrogens are also biologically active; they can markedly enhance
tumor cell proliferation."

1980 Drane HM and others. Oestrogenic activity of soya-bean
products. Food Cosmetics and Technology 1980 Aug ;18(4): 425-427. Sixteen
samples of soya-containing products were examined after the commercial
mouse diet was found to have estrogenic effects in laboratory mice, and
compared with the effects of DES on the weight of the mouse uterus. All
samples demonstrated estrogenic activity. The researchers attributed the
effects as equivalent to 16 ppb and 24 ppb DES in the two samples of human
food used.

1985 Jones and others. Naturally Occurring Estrogens
in Food--A Review. Journal of Food Additives and Contamination 1985;2(2):73-106.
That estrogen compounds in plants "induce estrus in immature animals
and interfere with normal reproductive processes has been know for more
than half a century. Consideration should be taken of any medium or long-term
changes in dietary habits which might be expected to increase the intake
of such phytoestrogens. The increasing use of vegetable proteins in general,
and in particular introduction of soy milk products for infant feeding
are two such examples."

1985 Setchell KD. Non Steroidal Estrogens of Dietary
Origin. Estrogens in the Environment, John A McLaughlin, ed. Elsevier,
1985: 69-83. "Since as little as 8 mg of genistein and 10 mg of daidzein
are sufficient to initiate uterotrophic effects in mice, it is not surprising
that the relatively large amounts of isoflavones present in soy protein
will readily explain the previously observed estrogenic effects in animals.
. . . The effects of plant estrogens in man should, however, be of some
concern since the newborn infant will be subject to chronic exposure to
soya milk, in some cases for up to two years. . . this situation could
be considered analogous to sheep grazing on clover."

1987 Hughes CI Jr. Effects of phytoestrogens on GnRH-induced
luteinizing hormone secretion in ovariectomized rats. Reprod Toxicol 1987-88;1(3):179-81.
"The dose potency of genistein appears to be approximately 1/10 that
of E2 [estradiol-17 beta] in this system. Phytoestrogens acutely perturb
reproductive and neuroendocrine function."

1987 Setchell, KD and others. Dietary estrogens -
a Probable Cause of Infertility and Liver Disease in Captive cheetahs.
Gastroenterology Aug 93(2): 225-233. Captive adult cheetahs consuming approximately
50 mg soy isoflavones per day from soy-based feed develop reproductive
failure and liver disease. When chicken-based feed was substituted for
soy-based feed, liver function improved. ". . . the relatively high
concentrations of phytoestrogens from soybean protein present in the commercial
diet fed to captive cheetahs in North American zoos may be one of the major
factors in the decline of fertility and in the etiology of liver disease
in this species. The survival of the captive cheetah population could depend
upon a simple change of diet by excluding exogenous estrogens."

1989 Kaldas RS and Hughes CL "Reproductive and
General Metabolic Effects of Phytoestrogens in Mammals" in Reproductive
Toxicology" Vol 3 pp -89 " these compounds might have a
role in the evolutionary success of herbivores, perhaps making the difference
between survival and extinction of species. We hypothesise that phytoestrogen-induced
physiologic and behavioral effects are significant factors in the reproductive
and therefore evolutionary success of species"

1989 Jones AE. Development and Application of High Performance
Chromatographic Method for the Analysis of Phytoestrogens. Jour Sci Food
Agric 1989;46:157-164. "It should be emphasised that the effects of
long-term low level exposure are unknown. . . . Vegetarians, vegans and
those relying on 'health' food preparations from alfalfa, legumes or soya
in particular would appear to be likely to regularly consume very much
higher levels of estrogens than those estimated for the population at large."

1992 Bulletin de L'Office Federal de la Santé
Publique, No 28, July 20, 1992. The Swiss health service estimates that
100 grams of soy protein provides the estrogenic equivalent of the contraceptive
pill.

1991 Atluru S and Atluru D. Evidence that Genistein,
a Protein-tyrosine Kinase Inhibitor, Inhibits CD28 Monoclonal-antibody-stimulated
Human T cell proliferation. Transplantation 1991 Feb;51(2):448-50. Genistein
blocks the production of T cells, needed for the immune system. The authors
conclude: " . . . that genistein is a powerful immunosuppressive agent.
. ." and suggest that it has a potential use in the treatment of allograft
rejection.

1992 Mayr U. Validation of Two In Vitro Test Systems
of Estrogenic Activities with Zearelenone, Phytoestrogens and Cereal Extracts.
Toxicology 1992;72:135-149. "Ingestion of these compounds causes diseases
of the reproductive system, reversible and irreversible infertility and
abnormal fetal development in all kinds of farm animals. Furthermore, an
inherent health risk to man cannot be excluded." This paper contains
graphs showing the crossover of phytoestrogens from estrogenic to anti-estrogenic
to toxic.

1992 Traganos F and others. Effects of genistein on the
growth and cell cycle progression of normal human lymphocytes and human
leukemic MOLT-4 and HL-60 cells. Cancer Res 1992 Nov 15;52(22):6200-8.
The results suggest that genistein "is expected to be a strong immunosuppressant."

1994 Cassidy A and others. Biological Effects of a
Diet of Soy Protein Rich in Isoflavones on the Menstrual Cycle of Premenopausal
Women. Am J Clin Nutr 1994 Sep;60(3):333-340 Six women with regular menstrual
cycles were given 60 grams soy protein containing 45 mg isoflavones daily.
After one month, all experienced delayed menstruation. Luteinizing hormone
and follicle-stimulating hormone were significantly suppressed. The effects
were similar to those of tamoxifen, an antiestrogen drug. Regular menstruation
did not resume until 3 months following the cessation of soy protein consumption.

1994 Packer AI and others. The ligand of the c-kit receptor
promotes oocyte growth. Dev Biol 1994 Jan;161 (1):194-205. "In the
presence of genistein, many of the follicles became disorganized and the
oocytes became partially denuded (Fig. 6B). There also appeared to be less
granulosa cell proliferation compared to the control follicles." This
statement appeared in the body of the report, not in the abstract.

1994 Setchell KD and others. Nonsteroidal estrogens
of dietary origin: possible roles in hormone-dependent disease. Am J Clin
Nutr 1984 Sep;40:569-78. Equol is a breakdown product of phytoestrogens
which shows up in the urine of individuals who eat soy. However, some subjects
are unable to breakdown phytoestrogens and equol does not show up in their
urine.

1994 Santti R and others. Developmental estrogenization
and prostatic neoplasia. Prostate 1994;24(2):67-78. Evidence indicates
that estrogen exposure during development may initiate cellular changes
in the prostate which would require estrogens and/or androgens later in
life for promotion of prostatic hyperplasia or neoplasia. ". . .
the critical time for estrogen action would be during the development of
the prostatic tissue. We further suggest that estrogen-sensitive cells
may remain in the prostate and be more responsive to estrogens later in
life or less responsive to the normal controlling mechanisms of prostatic
growth." In other words, exposure of the developing male child to
phytoestrogens in soy may make him more susceptible to prostate cancer
later in life.

1995 Makela SI and others. Dietary Soybean May Be Antiestrogenic
in Male Mice. J Nutr 1995 Mar;125(3):437-45. Soy isoflavones were found
to have antiestrogenic action in male mice.

1995 Woodhams DJ. Phytoestrogens and parrots: The
anatomy of an investigation. Proceedings of the Nutrition Society of New
Zealand. 1995, 20:22-30. Observations in aviaries and in handrearing of
parrots with bird-baby food were associated with parrot infertility, premature
sexual maturation and in some cases acute symptoms causing death. It was
noted that soy protein and/or soy meal were a constant ingredient in all
the diets used. This triggered an investigation into the literature on
the toxic effects of processed soy products. The first source consulted
was Soy Beans: Chemistry and Technology by Smith and Circle, an industry
test book published in 1972 that clearly listed a number of established
toxic effects with copi0us reference lists for each chapter.

1995 Irvine C and others. The Potential Adverse Effects
of Soybean Phytoestrogens in Infant Feeding. New Zealand Medical Journal.
1995 May 24:318. "Exposure to estrogenic compounds may pose a developmental
hazard in infants. . . particularly to the reproductive system. . . Neonates
are generally more susceptible than adults to perturbations of the sex
steroid milieu.

1995 Robertson IGC. Phytoestrogens: Toxicology and Regulatory
Recommendations. Proc Nutr Soc of NZ 1995;20:35-42. "Concerns have
been expressed about possible adverse effects, particularly to the foetal-neonatal
nervous and reproductive system. Adverse effects may occur by inhibition
of the enzyme which converts the relatively impotent estrone to the much
more potent oestradiol and by occupying the estrogen receptor resulting
in antagonism of the naturally produced oestradiol. Adequate oestradiol
is necessary for the imprinting and development of many physical, physiological
and behavioural characteristics during the neonatal period and infancy.
Infants on soy-based formula have been identified as a high risk group
because the formula is the main source of nutrient, and because of their
small size and developmental phase. Infants absorb phytoestrogens and have
a calculated daily dietary intake (per kg) 3-6 times that shown to have
physiological effects on women. . ."

1996 Petrakis NL and others. Stimulatory influence
of soy protein isolate on breast secretion in pre-and postmenopausal women.
Cancer Epidemiol Biomarkers Prev 1996 Oct;5(10):785-794. Twenty-four normal
pre- and postmenopausal white women, ages 30 to 58 were studied for one
year. During months 4-9, the women ingested 38 g soy protein isolate containing
38 mg genistein. Seven of the 24 women developed epithelial hyperplasia
during the period of soy feeding, a condition that presages breast cancer.
The authors noted that "the findings did not support our a priori
hypothesis" that soy protected Asian women against breast cancer.
"Instead, this pilot study indicates that prolonged consumption of
soy protein isolate has a stimulatory effect on the pre-menopausal female
breast, characterised by increased secretion of breast fluid, the appearance
of hyperplastic epithelial cells and elevated levels of plasma estradiol.
These findings are suggestive of an estrogenic stimulus from the isoflavones
genistein and diadzein contained in soy protein isolate."

1997 Dees C and others. Dietary estrogens stimulate
human breast cells to enter the cell cycle. Environ Health Perspect 1997
Apr;105 (Suppl 3):633-636. Dietary estrogens were found to increase enzymatic
activity leading to breast cancer. "Our findings are consistent with
a conclusion that dietary estrogens at low concentrations do not act as
anti-estrogens, but act like DDT and estradiol to stimulate human breast
cancer cells to enter the cell cycle.

1997 Wang C and Kurzer MS. Phytoestrogen concentration
determines effects on DNA synthesis in human breast cancer cells. Nutr
Cancer 1997;28(3):236-47. Although high levels of isoflavones inhibited
DNA synthesis in human breast cancer cells, low levels of genistein and
related compounds .. induced DNA synthesis 150-235%. "The current
focus on the role of phytoestrogens in cancer prevention must take into
account the biphasic effects observed in this study, showing inhibition
of DNA synthesis at high concentrations but induction at concentrations
close to probable levels in humans."

1997 Connolly JM and others. Effects of dietary menhaden
oil, soy, and a cyclooxygenase inhibitor on human breast cancer cell growth
and metastasis in nude mice. Nutr Cancer 1997;29(1):48-54. Phytoestrogens
at levels close to probable levels in humans were found to stimulate cellular
changes leading to breast cancer.

1997 Anderson D and others. Effect of various genotoxins
and reproductive toxins in human lymphocytes and sperm in the Comet assay.
Teratog Carcinog Mutagen 1997;17(1):29-43. Human sperm exposed to the phytoestrogen
diadzein had reduced DNA integrity. "The integrity of DNA is necessary
not only for the noncancerous state, but also for the accurate transmission
of genetic material to the next generation."

1997 Divi RL and others. Antithyroid Isoflavones from
the Soybean. Biochem Pharmacol 1997 Nov 15; 54:1087-96. This important
study identifies the goitrogenic compounds in soy as the isoflavones genistein
and daidzein, which were found to inhibit synthesis of thyroid hormone.
Inhibition of enzymes involved in the production of thyroid hormones occurred
at isoflavone levels "previously measured in plasma from humans consuming
soy products." "Because inhibition of thyroid hormones synthesis
can induce goiter and thyroid neoplasia in rodents, delineation of antithyroid
mechanisms for soy isoflavones may be important for extrapolating goitrogenic
hazards identified in chronic rodent bioassays to humans consuming soy
products." The authors note that "The soybean has been implicated
in diet-induced goiter by many studies."

1998 Sheehan DM. Herbal medicines, phytoestrogens and
toxicity:risk:benefit considerations. Proc Soc Exp Biol Med 1998 Mar;217(3):379-85.
Knowledge of toxicity is crucial to decrease the risk:benefit ratio but
herbal medicines and phytoestrogens in food are not tested as are drugs.
"Important toxicities with long latencies are particularly difficult
to associate with a causative agent. . . These considerations suggest that
much closer study in experimental animals and human populations exposed
to phytoestrogen-containing products, and particularly soy-based foods,
is necessary. Among human exposures, infant soy formula exposure appears
to provide the highest of all phytoestrogen doses, and this occurs during
development, often the most sensitive life-stage for induction of toxicity."

1998 Strauss L and others. Dietary phytoestrogens and
their Role in Hormonally Dependent Disease. Toxicol Lett 1998 Dec 28;102-103:349-54.
Although epidemiological studies suggest that diets rich in phytoestrogens
may be associated with low risk of breast and prostate cancer, there is
no direct evidence for the beneficial effects of phytoestrogens in humans.
It is plausible that phytoestrogens, as any exogenous hormonally active
agent, might also cause adverse effects in the endocrine system.

1998 Morris SM and others. p53, mutations, and apoptosis
in genistein-exposed human lymphoblastoid cells. Mutat Res 1998 Aug 31;405(1):41-56.
In vitro administration of genistein was found to cause cellular damage
and death. "Our results may be interpreted that genistein is a chromosomal
mutagen. . ."

1998 Santti R and others. Phytoestrogens: Potential
Endocrine Disrupters in Males. Toxicol Ind Health 1998 Jan-Apr;14(1-2):223-37.
In doses comparable to the daily intake from soy-based feed, isoflavonoids
such as genistein were estrogen agonists in the prostate of adult laboratory
rodents. When given neonatally, no persistent effects were observed. In
contrast, the central nervous system (CHS)-gonadal axis and the male sexual
behavior of the rat appear to be sensitive to phytoestrogens during development.
The changes were similar but not identical to those seen after neonatal
treatment with DES, but higher doses of phytoestrogens were needed.

1998 Setchell KD and others. Isoflavone content of
infant formulas and the metabolic fate of these early phytoestrogens in
early life. Am J Clin Nutr 1998 Dec;68(6 Suppl):1453S-1461S. Plasma isoflavone
levels in infants fed soy-based formula were 13,000-22,000 higher than
concentrations found in fed breast milk or milk-based formula. These high
levels are explained "by reduced intestinal biotransformation, as
evidenced by low or undetectable concentrations of equol and other metabolites,
and is maintained by constant daily exposure from frequent feeding."
The authors assert that these unnaturally high levels of isoflavones in
the bloodstreams of soy-fed children "may have long-term health benefits
for hormone-dependent diseases."

1998 McMichael-Phillips DF and others. Effects of soy-protein
supplementation on epithelial proliferation in the histologically normal
human breast. Am J Clin Nutr 1998 Dec;68(6 Suppl):1431S-1435S. Forty-eight
women with benign or malignant breast disease were randomly assigned a
normal diet either alone or with a 60 gram soy supplement containing 45
mg isoflavones, taken for 14 days. The proliferation rate of breast lobular
epithelium significantly increased after just 14 days of soy supplementation
when both the day of menstrual cycle and age of patient were accounted
for. Thus short-term dietary soy containing isoflavone levels found in
modern soy foods stimulates breast proliferation.

1998 Strauss and others. Genistein exerts estrogen-like
effects in make mouse reproductive tract. Mol Cell Endocrinol 1998 Sept
25;144(1-2):83-93. Genistein was found to have estrogenic effects in adult
male mice, at doses comparable to those present in soy-based human diets.
In neonatal animals, considerably higher doses are required to show estrogen-like
activity.

1999 Casanova M and others. Developmental effects of
dietary phytoestrogens in Sprague-Dawley rats and interactions of genistein
and daidzein with rat estrogen receptors alpha and beta in vitro. Toxicol
Sci 1999 Oct;51(2):236-44. Effects of dietary genistein included a decreased
rate of body-weight gain, a markedly increased (2.3 fold) uterine/body
weight and a significant acceleration of puberty among females.

1999 Fisher JS and others. Effect of neonatal exposure
to estrogenic compounds on development of the excurrent ducts of the rat
testis through puberty to adulthood. Environ Health Perspect 1999 May;107(5):397-405.
Administration of genistein to rats caused minor but significant changes
in rat testes. "This study suggests that structural and functional..
.development of the excurrent ducts is susceptible to impairment by neonatal
estrogen exposure, probably as a consequence of direct effects. The magnitude
and duration of adverse changes induced by treatment with a range of estrogenic
compounds was broadly comparable to their estrogenic potencies reported
from in vitro assays."

1999 Kulling SE and others. The phytoestrogens coumoestrol
and genistein induce structural chromosomal aberrations in cultured human
peripheral blood lymphocytes. Arch Toxicol 1999 Feb;73(1):50-4. Exposure
of blood lymphocytes to low levels of genistein in vitro caused chromosomal
aberrations including chromatid breaks, gaps and interchanges. Exposure
to daidzein did not cause aberrations, even at high levels. The results
suggest that ". . . some but not all phytoestrogens have the potential
for genetic toxicity."

1999 Hilakavi-Clarke and others Exposure to genisten
during pregnancy increases carcinogen-induced mammary tumorigenesis in
female rat offspring. Oncol Rep 1999 Sep-Oct;6(5):1089-95. Dietary genistein
was found to enhance the growth of mammary gland tumors in mice. The results
suggest ". . . that a maternal exposure to subcutaneous administration
of genistein can increase mammary tumorigenesis in the offspring, mimicking
the effects of in utero estrogen exposures."

1999 Nagata C and others. Hot flushes and other menopausal
symptoms in relation to soy product intake in Japanese women. Climacteric
1999 Mar;2(1):6-12. Intake of fermented soy products was found to reduce
the severity of hot flashes in Japanese women, but not total soy intake
(from unfermented soy products such as are found in western diets). This
study is included because it contradicts assertions that Japanese women
do not suffer from hot flashes.

2000 Cassanova N and others. Comparative effects of
neonatal exposure of male rats to potent and weak (environmental) estrogens
on spermatogenesis at puberty and the relationship to adult testis size
and fertility: evidence for stimulatory effects of low estrogen levels.
Endocrinology 2000 Oct;141(10):3898-907. Administration of genistein to
rats significantly retarded most measures of pubertal spermatogenesis.
Animals fed a soy-free diet had significantly larger testes than controls
fed a soy-containing diet. "It is concluded that. . . the presence
or absence of soy or genistein in the diet has significant short-term (pubertal
spermatogenesis) and long-term (body weight, testis size, FSH levels and
possibly mating) effects on males.

2000 Watanabe S and others. Effects of isoflavone supplement
on healthy women. Biofactors 2000;12(1-4):233-41. After one month of taking
20 mg or 40 mg isoflavones daily, 60% of the young women had prolonged
menstruation, 20% had shortened menstruation, 17% remained unchanged and
3% became irregular. Other hormonal changes "suggest that isoflavones
influence not only estrogen receptor-related functions but the hypothalamo-hypophysis-gonadal
axis."

2000 Strick R and others. Dietary bioflavonoids induce
cleavage in the MLL gene and may contribute to infant leukemai. Proc Natl
Acad Sci USA 2000 Apr 25;97(9):4790-5. Researchers found that flavonoids,
especially genistein, can cross the placenta and induce cell changes that
lead to infant leukemia.

2000 Chang HS and Doerge DR. Dietary genistein inactivates
rat thyroid peroxidase in vivo without an apparent hypothyroid effect.
Toxicol Appl Pharmacol 2000 Nov 1;168(3):244-52. The activity of thyroid
peroxidase activity in soy-fed rats was reduced by up to 80% compared to
those on a soy-free diet. As thyroid hormone levels and thyroid weights
were no different between treated and untreated groups, the researchers
concluded that "the remaining enzymatic activity is sufficient to
maintain thyroid homeostasis in the absence of additional perturbations."
"However, it is difficult or impossible to measure some of the more
subtle manifestations of hypothyroidism in rats".

2000 Habito RC and others. Effects of replacing meat
with soyabean in the diet on sex hormone concentrations in healthy adult
males. Br J Nutr 2000 Oct;84(4):557-63. Men consuming tofu instead of meat
for 4 weeks had lower testosterone-oestradiol ratios as well as changes
in other hormone levels. "Thus, replacement of meat protein with soyabean
protein, as tofu, may have a minor effect on biologically-active sex hormones
which could influence prostate cancer risk."

2001 Doerge DR and others. Placental transfer of the
soy isoflavone genistein following dietary and gavage administration to
Sprague Dawley rats. Reprod Toxicol 2001 Mar-Apr;15(2):105-10. Genistein
was found to cross the rat placenta and reach the fetal brain in doses
similar to those observed in humans.

2001 Newbold RR and others. Uterine adenocarcinoma
in mice treated neonatally with genistein. Cancer Res 2001 Jun 1;61(11):4325-8.
Genistein in soy was found to be more carcinogenic than DES, especially
during "critical periods of differentiation.. . . the use of soy-based
infant formulas in the absence of medical necessity and the marketing of
soy products designed to appeal to children should be closely examined."

2001 Declos KB and others. Effects of dietary genistein
exposure during development on male and female DC (Sprague-Dawley) rats.
Reprod Toxicol 2001 Nov;15(6):647-63. Genistein was administered to rats
at various concentrations starting on gestation day 7 and continuing throughout
pregnancy, lactation and growth of the pups to day 50. The genistein-fed
rats showed a number of variances from the norm: lower weight in both sexes;
decreased prostate weight in males; higher pituitary gland to body weight
ratios in both sexes; hyperplasia of the mammary glands, abnormal ovarian
antral follicles and abnormal cellular maturation in the vagina in females;
aberrant or delayed spermatogenesis and deficit sperm in males; and an
increase in the incidence and/or severity of renal tubal mineralisation
in both sexes, even at low doses. "Dietary genistein thus produced
effects in multiple estrogen-sensitive tissues in males and females that
are generally consistent with its estrogenic activity. These effects occurred
within exposure ranges achievable in humans."

2001 Thigpen JE and others. Effects of the dietary
phytoestrogens daidzein and genistein on the incidence of vulvar carcinomas
in 129/J mice. Cancer Detect Prev 2001;25(6):527-32. Within one month,
the incidence of vulvar carcinomas in mice fed a modified soy protein diet
was significantly increased over those of mice fed control diets. Within
three months, the incidence of vulvar carcinomas in mice fed the soy protein
diet was significantly increased over those of mice fed other control diets.
"We concluded that dietary levels of daidzein and genistein were associated
with an increase in the incidence of vulvar carcinomas in mice. . ."

2001 de Lemos ML. Effects of soy phytoestrogens genistein
and daidzein on breast cancer growth. Ann Pharmacother 2001 Sep;35(9):118-21.
"Genistein and daidzein may stimulate existing breast tumor growth
and antagonize the effects of tamoxifen. Women with current or past breast
cancer should be aware of the risks of potential tumor growth when taking
soy products."

2001 Nagao T and others. Reproductive effects in male
and female rats of neonatal exposure to genistein. Reprod Toxicol 2001
Jul-Aug;15(4):399-411. Feeding of genistein to newborn rats resulted in
lower body weight in male and female rats, estrous cycle irregularities
and lowered fertility in female rats. Neonatal exposure to genistein caused
dysfunction of postpubertal reproduction performance as well as abnormal
development of gonads in female but not in male rats.

2001 Slikker W Jr and others. Gender-based differences
in rats after chronic dietary exposure to genistein. Int J Toxicol 2001
May-Jun;20(3):175-9. Dose-related alternations of the volume of the sexually
dimorphic nucleus of the medial preoptic area were observed in genistein-exposed
male rats but not females.

2001 den Tonkelaar I and others. Urinary phytoestrogens
and postmenopausal breast cancer risk. Cancer Epidemiol Biomarkers Prev
2001 Mar;10(3):223-8. "We were not able to detect the previously reported
protective effects of genistein and enterolactone on breast cancer risk
in our postmenopausal population of Dutch women."

2001 Bennetau-Pelissero C and others. Effect of genistein-enriched
diets on the endocrine process of gametogenesis and on reproduction efficiency
of the rainbow trout Oncorhynchus mykiss. Gen Comp Endocrinol 2001 Feb;121(2):173-87.
Genistein caused a decrease in testosterone levels in rainbow trout. Testicular
development was accelerated in genistein-fed fish and sperm motility and
concentration were decreased in a dose-dependent manner at spawning.

2001 Patisual HB and others. Soy isoflavone supplements
antagonize reproductive behavior and estrogen receptor alpha- and beta-dependent
gene expression in the brain. Endocrinology 2001 Jul;142(7):2946-52. Soy
isoflavones interfere with estrogen receptors in the adult female rat brain
resulting in a significant decrease in receptive behavior in estrogen-
and progesterone-primed females. "The observed disruption of sexual
receptivity by the isoflavone supplement is probably due to antiestrogenic
effects observed in the brain."

2001 Whitten PL and Patisaul HB. Cross-species and interassay
comparisons of phytoestrogen actions. Environ Health Perspect 2001 Mar;109
Suppl 1:5-20. "In vivo data show that phytoestrogens have a wide range
of biologic effects at doses and plasma concentrations seen with normal
human diets. Significant in vivo responses have been observed in animal
and human tests for bone, breast, ovary, pituitary, vasculature, prostate
and serum lipids. . . . Steroidogenesis and the hypothalamic-pituitary-gonadal
axis appear to be important loci of phytoestrogen actions, but these inferences
must be tentative because good dose-response data are not available for
many end points."

2001 Shibayama T and others. Neonatal exposure to genistein
reduces expression of estrogen receptor alpha and androgen receptor in
testes of adult mice. Endocr J 2001 Dec;48(6):655-63. "Our results
exhibited that the disruption of gene expression continued for long term
such as 3 months after administration of genistein, even if no effect was
found at conventional reproductive-toxicological levels. We have shown
that neonatal administration of weak estrogenic compound (genistein) affects
male reproductive organs at molecular levels in adulthood."